The present invention generally relates to antiviral agents useful for inhibiting the infectivity of human acquired immunodeficiency virus. More particularly, the present invention concerns synthetic polypeptides capable of inhibiting the infectivity of HIV-1.
Acquired Immunodeficiency Syndrome (AIDS), caused by the HIV-1 virus, has been reported in increasing numbers throughout the world. The disease is currently recognized by medical experts as approaching epidemic proportions and there is presently no cure or vaccine available to control its spread. Furthermore, new strains are developing due to the high mutation rate of the virus. Consequently, there is a tremendous need for methods of treating HIV-infected individuals and for the prevention of HIV-1 infections.
Until recently, research efforts directed toward developing anti-HIV agents has focused on several approaches. These approaches include: (1) the development of polyclonal or monoclonal antibodies to HIV antigens; (2) chemical antiviral agents; and (3) a soluble CD4 molecule corresponding to the HIV receptor on CD4.sup.+ target cells.
For example, previous research efforts have yielded both monoclonal and polyclonal antibodies to various HIV proteins. In particular, envelope glycoproteins of the HIV-1 virus, such as gp160, have been found to elicit antibodies which neutralize the infectivity of HIV-1. Consequently, gp160 and various fragments thereof have been tested extensively as candidates for a potential vaccine against HIV-1 infections. Unfortunately, it has been found that some of the immunodominant regions present on gp160 elicit the production of harmful antibodies which may trigger undesirable immunosuppression or even enhance HIV-1 infections.
For example, it is well-known that gp160 is a glycosylated polypeptide which has a molecular weight of 160,000 daltons and is processed to yield envelope glycoproteins gp120 and gp41. Although gp120 and gp41 both elicit immune responses which result in antibodies to HIV-1, these responses are generally immuno-specific to individual sub-types of the virus or may cause undesirable immunosuppressive effects. In particular, certain selected regions from gp120 and gp41 can suppress lymphocyte blastogenic responses and inhibit the activity of natural killer T-cells. Furthermore, some of the immunodominant regions of gp120 and gp41 do not contribute to protective immunity and may behave as immunological decoys.
An additional problem is encountered in developing a vaccine which is effective against HIV-1 infections because the virus exhibits frequent sequence variations during replication. More specifically, individual HIV-1 virus isolates demonstrate sequence variations, particularly in critical immunodominant regions of the virus sequence. Consequently, most virus-neutralizing antibodies are immuno-specific to individual clinical sub-types of the virus and the antibodies elicited by a vaccination against one clinical sub-type would likely be ineffective against another strain of the virus.
Other research efforts have been directed toward developing chemical agents which are effective against HIV-1 infections. For example, 3'azido-3'deoxythymidine (AZT) and other dideoxynucleoside analogs have been used to treat HIV-1 infections, however, these drugs are used in dosages which are often toxic to the patient. Furthermore, the use of chemical agents frequently induces the formation of viral mutants that are drug-resistant. Viral replication of drug-resistant mutants is not effectively inhibited by these drugs.
Additional research efforts have been directed toward the development of synthetic molecules containing receptor sites that mimic the receptor sites on target cells which the HIV-1 virions use to attach themselves to the cell membrane. For example, the CD4 molecule was expected to become the most hopeful anti-HIV agent for both therapy and prophylaxis of HIV-1 infections since it effectively inhibited viral replication in vitro. Unfortunately, it was later discovered that the molecule was not capable of inhibiting the infectivity of many clinical sub-types or strains of the virus.
It is therefore an object of the present invention to provide an antiviral substance which is capable of effectively inhibiting the replication of HIV-1, HIV-1-mediated cytopathogenesis and cell fusion at a concentration which falls within acceptable limits of cytotoxicity.
It is a further object of the present invention to provide an antiviral substance which is not specific to only one sub-type of HIV-1, but is effective against a variety of sub-types or strains of the virus.
It is still a further object of the present invention to provide an antiviral substance which is effective against AZT-resistant variants of HIV-1.
It is also an object of the present invention to provide a method of treating HIV-1 infections in a subject without inducing undesirable immunosuppressive effects.